A Novel Approach to Explore Metabolic Diseases: Neddylation

Protein post translational modification (PTM) is the main regulatory mechanism for eukaryotic cell function, among which ubiquitination is based on the reversible degradation of proteins by the ubiquitin proteasome system to regulate cell homeostasis. The neural precursor cell expressed developmental downregulated gene 8 (NEDD8) is a kind of ubiquitin like protein that shares 80% homology and 60% identity with ubiquitin. The PTM process by covalently binding NEDD8 to lysine residues in proteins is called neddylation. The neddylation reaction could be regulated by NEDD8, its precursors, substrates, E1 activating enzymes, E2 binding enzymes, E3 ligases, de-neddylases, and its inhibitors, such as MLN4924. NEDD8 is widely expressed in the whole cell structure of multiple tissues and species, and neddylation related factors are highly expressed in metabolism related adrenal glands, thyroid glands, parathyroid glands, skeletal muscles, myocardium, and adipose tissues, related to metabolic cardiovascular, cerebrovascular and liver diseases, adipogenic and osteogenic differentiation, as well as tumor glycolysis and glucose metabolism resulting from angiogenesis and endothelial disfunction, hepatotoxicity, adipogenesis, osteogenesis, Warburg effect, and insulin function. This review provides researchers with a new approach to explore metabolic diseases via searching and analyzing the histological, cytological, and subcellular localization of neddylation specific molecules in databases, and exploring specific mechanism neddylation mediating metabolic diseases by searching for neddylation related terms with the development of pre-clinical neddylation pharmacological inhibitors.